ABSTRACT Thyroid hormone (TH) molecules enter cells via membrane transporters and, depending on the cell type, can be activated, that is thyroxine (T4) to 3,5,3'-tri-iodothyronine (T3) conversion, or inactivated - T3 to 3,3'-diiodo-L-thyronine (T2) or T4 to reverse tri-iodothyronine (rT3) conversion. These reactions are catalyzed by the deiodinases. The biologically active hormone, T3, eventually binds to intracellular TH receptors (TR), TR? and TR?, and initiates TH signaling, i.e. regulation of target genes and other metabolic pathways. At least three families of transmembrane transporters, MCT, OATP and LAT, facilitate the entry of TH into cells, which follow the gradient of free hormone between the extracellular fluid and the cytoplasm. Inactivation or marked downregulation of TH transporters can dampen TH signaling. At the same time, dynamic modifications in the expression or activity of TRs and transcriptional co-regulators can affect positively or negatively the intensity of TH signaling. However, the deiodinases are the element that provides greatest amplitude in dynamic control of TH signaling. Cells that express the activating deiodinase DIO2 can rapidly enhance TH signaling due to intracellular build-up of T3. In contrast, TH signaling is dampened in cells that express the inactivating deiodinase DIO3. This explains how THs can regulate pathways in development, metabolism and growth, despite rather stable levels in the circulation. As a consequence, TH signaling is unique for each cell (tissue or organ), depending on circulating TH levels and on the exclusive blend of transporters, deiodinases and TRs present in each cell. In this proposed project we explore the key mechanisms underlying customization of TH signaling during development, in health and in disease states.